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The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-β (Aβ) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimer's disease (AD). While it is known that the posttranslational modifications of Aβ have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated Aβ3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor α and synapse loss. Here we report that Aβ3(pE)-42, but not Aβ1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome-dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with a lysosomal protease inhibitor, E-64, rescues GFAP upregulation, NF-κB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that Aβ3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Objective: The scavenger receptor CD36 is injurious in acute experimental focal stroke and neurodegenerative diseases in the adult. We investigated the effects of genetic deletion of CD36 (CD36ko) on acute injury, and oxidative and inflammatory signaling after neonatal stroke., Methods: Postnatal day 9 CD36ko and wild-type (WT) mice were subjected to a transient middle cerebral artery occlusion (MCAO). Injury, phagocytosis of dying cells, and CD36 inflammatory signaling were determined., Results: While the volume of tissue at risk by diffusion-weighted magnetic resonance imaging during MCAO was similar in neonatal CD36ko and WT mice, by 24 hours after reperfusion, injury was more severe in CD36ko and was associated with increased caspase-3 cleavage and reduced engulfment of neurons expressing cleaved caspase-3 by activated microglia. No significant superoxide generation was observed in activated microglia in injured WT, whereas increased superoxide production in vessels and nuclear factor (NF)-κB activation induced by MCAO were unaffected by lack of CD36. Lyn expression was higher in injured CD36ko, and cell type-specific patterns of Lyn expression were altered; Lyn was expressed in endothelial cells and microglia in WT but predominantly in dying neurons in CD36ko., Interpretation: Lack of CD36 results in poorer short-term outcome from neonatal focal stroke due to lack of attenuation of NF-κB-mediated inflammation and diminished removal of apoptotic neuronal debris. Although inhibition of CD36 does not seem to be a good therapeutic target for protection after acute neonatal stroke, as it is after adult stroke, seeking better understanding of CD36 signaling in particular cell populations may reveal important therapeutic targets for neonatal stroke., (Copyright © 2012 American Neurological Association.)

Is there a correlation between the 6-min walk and aerobic fitness in children? We studied healthy and cystic fibrosis (CF) subjects age 8-20 years using the 6-min walk test, treadmill graded exercise stress test, and spirometry. Six-minute walk distance (6MWD) and the product of 6MWD and body weight (6MWORK) were related to aerobic capacity. Data were analyzed using Student's t-test and Pearson correlation. 13 healthy subjects [9 females, mean age 15.8 +/- 3.6 years, % predicted forced expiratory volume in one second (FEV(1)) 105 +/- 12%, 6MWD 557 +/- 73 m, peak oxygen uptake (V' O2 max) 41.4 +/- 7.2 ml/kg/min, and heart rate (HR) at V' O2 max 180 +/- 10] and 11 CF subjects (3 females, mean age 14.3 +/- 3.8 years, FEV(1) 67 +/- 25.9%, 6MWD 468 +/- 68 m, V' O2 max 27.0 +/- 8.1 ml/kg, and HR at V' O2 max 163 +/- 22] were studied. 6MWD correlates with V' O2 max in normal subjects (r = 0.59, P < 0.05) but not in CF subjects (r = 0.09, NS). 6MWORK correlates with V' O2 max in CF subjects (r = 0.65, P < 0.05) but not in normal subjects (r = 0.278, NS). We conclude that the 6MWD corresponds with aerobic fitness in normal pediatric subjects and 6MWORK corresponds with aerobic fitness in CF subjects. We speculate that 6MWORK is superior to 6MWD for assessment of aerobic fitness in children with CF., ((c) 2010 Wiley-Liss, Inc.)

Aberrant expression of matrix metalloproteinase-9 (MMP-9) is implicated in the process of invasion and angiogenesis of malignant tumors as well as in inflammatory diseases of the CNS. Therefore, the development of compounds that can inhibit or suppress MMP-9 is required to treat brain tumors. We investigated the effects of a ginseng saponin metabolite, compound K (20-O-(beta-D-glucopyranosyl)-20(S)-protopanaxadiol), on MMP-9 expression in human astroglioma cells. Compound K significantly inhibited the secretion and protein expression of MMP-9 induced by PMA. The inhibitory effect of compound K on MMP-9 expression correlated with decreased MMP-9 mRNA levels and suppression of MMP-9 promoter activity. The compound K-mediated inhibition of MMP-9 gene expression appears to occur via AP-1 because its DNA-binding and transcriptional activities were suppressed by the agent. Furthermore, compound K significantly repressed the PMA-mediated activation of p38 MAPK, ERK and JNK, which are upstream modulators of AP-1. Finally, compound K inhibited the in vitro invasiveness of glioma cells. Therefore, inhibition of MMP-9 expression by compound K might have therapeutic potential for controlling the growth and invasiveness of brain tumors., (Copyright 2005 Wiley-Liss, Inc.)

An abrupt onset of a neurological deficit is a rare occurrence in patients with cystic fibrosis (CF). As many CF patients have indwelling intravenous catheters, one of the complications may be deep venous thrombosis. Cerebral thromboembolism through an intracardiac shunt should be considered in CF patients who develop unexplained acute neurological deficits. We report on the case of a 19-year-old CF patient with insulin-dependent diabetes mellitus who was on oral contraceptives and had a Port-A-Cath(R) in place. The patient developed an acute neurological deficit after pulmonary function testing. Radiologic investigations of her head and neck were unremarkable, except for bilateral maxillary and ethmoid sinusitis. An electroencephalogram showed epileptiform discharges primarily from the right hemisphere. A transthoracic echocardiogram (TTE) revealed a small thrombus in the right atrium. A transesophageal echocardiogram (TEE) demonstrated a left-to-right shunt through a patent foramen ovale (PFO) that was not found by TTE. Extensive investigation to rule out congenital and acquired thrombophilia was negative. Treatment consisted of aspirin and discontinuation of oral contraceptives and vitamin K supplementation. Spontaneous complete recovery of the neurological deficits occurred within 24 hr after onset of symptoms.We conclude that paradoxical embolism should be in the differential diagnoses of CF patients who have indwelling intravenous catheters and who develop an unexplained stroke. An extensive investigation to rule out intracardiac abnormalities and thrombophilia should be considered. The risks and benefits of PFO closure vs. prophylactic anticoagulant and antiplatelet aggregation treatment in this group of patients should be carefully weighed., (Copyright 2003 Wiley-Liss, Inc.)

The correlation between digital clubbing and certain pulmonary function derangements (hypoxemia and FEV(1)) was previously described. However, the relationship between digital clubbing and other measures of pulmonary function or the presence of liver disease in patients with cystic fibrosis (CF) is poorly defined. Hence we compared the digital clubbing index (CI: ratio of distal phalangeal depth to interphalangeal depth) of 100 patients with CF (43 males, 57 females; mean age, 15.7 +/- 7.3 years) with that of 100 age- and gender-matched healthy controls. Digital clubbing was defined as a CI > or = 1.00 (mean + 2.6 SD; 99% of normal subjects). The CI and its relationship to pulmonary function and to liver disease was then evaluated in the CF patients. Digital clubbing was present in 75/100 (75%) of CF patients but was absent in all controls (P < 0.0001). In CF patients, CI was inversely correlated with PaO(2) (r = -0.555; P < 0.001), FEV(1) (r = -0.499; P < 0.001), and FEF(25-75%) (r = -0.404; P < 0.001), and was positively correlated with RV (r = 0.285; P < 0.05) and the slope of phase 3 of single-breath nitrogen washout (SP3N(2)) (r = 0.532; P < 0.01). There was no significant correlation between CI and age (r = 0.020; P = 0.84), TLC (r = -0.097; P = 0.34), PaCO(2) (r = 0.167; P = 0.10), or history of liver disease (P = 0.08). We conclude that in CF, the degree of digital clubbing is related to degree of hypoxemia, airways obstruction, hyperinflation, and nonuniformity of ventilation.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a common autosomal recessive disease in Caucasians. The broad mutation spectrum varies among different patient groups. Current molecular diagnoses are designed to detect 80-97% of CF chromosomes in Caucasians and Ashkenazi Jews but have a much lower detection rate in Hispanic CF patients. Grebe et al. [1994] reported a 58% detection rate in Hispanic patients. Since then, there has been no large-scale, complete mutational analysis of Hispanic CF patients. In this study, the mutations in 62 Hispanic patients from southern California were investigated. The entire coding and flanking intronic regions of the CFTR gene were analyzed by temporal temperature gradient gel electrophoresis (TTGE) followed by sequencing to identify the mutations. Eleven novel mutations were discovered in this patient group: 3876delA, 406-1G>A, 935delA, 663delT, 3271delGG, 2105-2117del13insAGAAA, 3199del6, Q179K, 2108delA, 3171delC, and 3500-2A>T. Among the mutations, seven were out-of-frame insertions and deletions that result in truncated proteins, two were splice-site mutations, one was an in-frame 6 bp deletion, and one was a missense mutation that involved the non-conservative change of glutamine-179 to lysine. All patients presented severe classical clinical course with pancreatic insufficiency and poor growth, consistent with the nature of truncation mutation. The results indicate that TTGE screening following the analysis of recurrent mutations will substantially improve the mutation detection rate for Hispanic CF patients from southern California., (Copyright 2001 Wiley-Liss, Inc.)